Scientific Publications

The CCR5 co-receptor binds to the HIV-1 gp120 envelope glycoprotein and facilitates HIV-1 entry into cells. Its N terminus is tyrosine-sulfated, as are many antibodies that react with the co-receptor binding site on gp120. We applied nuclear magnetic resonance and crystallographic techniques to analyze the structure of the CCR5 N terminus and that of the tyrosine-sulfated antibody 412d in complex with gp120 and CD4. The conformations of tyrosine-sulfated regions of CCR5 (alpha-helix) and 412d (extended loop) are surprisingly different. Nonetheless, a critical sulfotyrosine on CCR5 and on 412d induces similar structural rearrangements in gp120. These results now provide a framework for understanding HIV-1 interactions with the CCR5 N terminus during viral entry and define a conserved site on gp120, whose recognition of sulfotyrosine engenders posttranslational mimicry by the immune system.

Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.

We have identified several patient sera showing potent and broad HIV-1 neutralization. Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4-binding region of HIV-1 gp120. Novel antibodies to the CD4-binding site are elicited in some HIV-1-infected individuals, and new approaches to present this conserved region of gp120 to the immune system may result in improved vaccine immunogens.

This study was conducted to compare viral dynamics in blood and semen between subjects with antibody negative, acute HIV-1 infection and other subjects with later stages of infection.

The identification of cross-neutralizing antibodies to HIV-1 is important for designing antigens aimed at eliciting similar antibodies upon immunization. The monoclonal antibody (mAb) F425-B4e8 had been suggested previously to bind an epitope at the base of V3 and shown to neutralize two primary HIV isolates. Here, we have assessed the neutralization breadth of mAb F425-B4e8 using a 40-member panel of primary HIV-1 and determined the epitope specificity of the mAb. The antibody was able to neutralize 8 clade B viruses (n=16), 1 clade C virus (n=11), and 2 clade D viruses (n=6), thus placing it among the more broadly neutralizing anti-V3 antibodies described so far. Contrary to an initial report, results from our scanning mutagenesis of the V3 region suggest that mAb F425-B4e8 interacts primarily with the crown/tip of V3, notably Ile(309), Arg(315), and Phe(317). Despite the somewhat limited neutralization breadth of mAb F425-B4e8, the results presented here, along with analyses from other cross-neutralizing anti-V3 mAbs, may facilitate the template-based design of antigens that target V3 and permit neutralization of HIV-1 strains in which the V3 region is accessible to antibodies.

A new model was developed to examine the potential impacts of an AIDS vaccine in developing countries. The findings suggest that even a modestly efficacious first-generation vaccine could have a profound effect on the AIDS pandemic. A vaccine with 50 percent efficacy provided to 30 percent of the population would reduce new annual infections by 34 percent (seventeen million infections avoided) over fifteen years and result in substantial financial savings. A more efficacious vaccine, combined with expanded delivery, would do even more to control the pandemic. It therefore makes sense to continue investing in AIDS vaccine research and development and the eventual manufacture and widespread distribution of a vaccine.

Men who have sex with men (MSM) are highly vulnerable to HIV infection, but this population can be particularly difficult to reach in sub-Saharan Africa. We aimed to estimate the number of MSM who sell sex in and around Mombasa, Kenya, in order to plan HIV prevention research.

CD4 Th cells play critical roles in stimulating Ab production and in generating primary or maintaining memory CTL. The requirement for CD4 help in generating and maintaining CTL responses has been reported to vary depending on the vector or method used for immunization. In this study, we examined the requirement for CD4 T cell help in generating and maintaining CTL responses to an experimental AIDS vaccine vector based on live recombinant vesicular stomatitis virus (VSV) expressing HIV Env protein. We found that primary CD8 T cell responses and short-term memory to HIV Env and VSV nucleocapsid (VSV N) proteins were largely intact in CD4 T cell-deficient mice. These responses were efficiently recalled at 30 days postinfection by boosting with vaccinia recombinants expressing HIV Env or VSV N. However, by 60 days postinfection, the memory/recall response to VSV N was lost in CD4-deficient mice, while the recall response HIV Env was partially maintained in the same animals for at least 90 days. This result indicates that there are epitope-specific requirements for CD4 help in the maintenance of memory CD8 T cell responses. Our results also suggest that choice of epitopes might be critical in an AIDS vaccine designed to protect against disease in the context of reduced or declining CD4 T cell help.

The purpose of this article is to describe the requirements for clinical laboratories supporting large-scale multinational trials of prophylactic AIDS vaccine trials and review the progress made.